Cancer stem cell targeted therapies.

In normal dividing tissues, cell homeostasis is maintained by rare cellular elements, the stem cells, that have the unique property of self-renewal and differentiation to generate a population of functionally mature tissue elements. Recent studies carried out in the last three decades support the existence of stem cells also in tumors, the so-called cancer stem cells. Cancer stem cells have the property of initiating and maintaining tumor growth, are able to self-renew and to differentiate, are the main drivers of intra- and inter-tumoral heterogeneity and the main cellular mediators of drug resistance, leading to tumor recurrence and metastasis. Cancer stem cells can be identified in many tumors according to specific immunophenotypic features, but cancer stemness cannot be defined as a fixed property, due to cancer plasticity. For these properties, cancer stem cells represent attractive targets for developing new anti-cancer therapies and there is supporting evidence that the combination of conventional anticancer therapies with drugs targeting cancer stem cells could lead to cancer eradication. Ongoing studies in some tumors strongly support the clinical utility of developing efficient strategies of cancer stem cell targeting.

Insights into the manifestations, outcomes, and mechanisms of leukemogenesis in Down syndrome.

Children with Down syndrome (DS) show a spectrum of clinical anomalies, including cognitive impairment, cardiac malformations, and craniofacial dysmorphy. Moreover, hematologists have also noted that these children commonly show macrocytosis, abnormal platelet counts, and an increased incidence of transient myeloproliferative disease (TMD), acute megakaryocytic leukemia (AMKL), and acute lymphoid leukemia (ALL). In this review, we summarize the clinical manifestations and characteristics of these leukemias, provide an update on therapeutic strategies and patient outcomes, and discuss the most recent advances in DS-leukemia research. With the increased knowledge of the way in which trisomy 21 affects hematopoiesis and the specific genetic mutations that are found in DS-associated leukemias, we are well on our way toward designing improved strategies for treating both myeloid and lymphoid malignancies in this high-risk population.

Pancytopenia presenting with monosomy 7 which disappeared after immunosuppressive therapy.

Monosomy 7 syndrome in infant is considered as pre-leukemic condition of poor prognosis. However, it seems controversial recently, because some cases of monosomy 7 syndrome showed spontaneous remission. We report 2-year-old girl with severe pancytopenia, who presented with monosomy 7. Morphologically, there was little dysplasia in the trilineage hematopoiesis. Monosomy 7 clone of CD34 positive cells, bone marrow mononuclear cells (BMMNC), and peripheral nuclear cells was 4.0, 40, and 3.8%, respectively. Immunosuppressive therapy was effective along with the disappearance of monosomy 7 clone. WT1 mRNA expression was not increased in monosomy 7 clone. Pathogenesis of monosomy 7 and its relation to aplastic anemia is discussed.

Polymorphisms within glutathione S-transferase genes (GSTM1, GSTT1, GSTP1) and risk of relapse in childhood B-cell precursor acute lymphoblastic leukemia: a case-control study.

Glutathione S-transferases (GSTs) have been associated with outcome in human cancers treated with cytotoxic chemotherapy. In a case-control study, we investigated the association between polymorphisms within the GSTM1, GSTT1, and GSTP1 genes and risk of relapse in childhood acute lymphoblastic leukemia (ALL). Cases were relapsed patients. Controls were successfully treated patients with a minimum follow-up of 5 years. The null genotype (absence of both alleles) for GSTM1 or GSTT1 conferred a 2-fold (OR = 0.5, 95% CI = 0. 23-1.07, P =.078) and 2.8-fold (OR = 0.36, 95% CI = 0.13-0.99, P =. 048) reduction in risk of relapse, respectively, relative to the presence of the GSTM1 or GSTT1 gene. The GSTP1 Val(105)/Val(105) genotype showed a 3-fold decrease in risk of relapse (OR = 0.33, 95% CI = 0.09-1.23, P =.099) in comparison to the combined category of Ile(105)/Val(105) and Ile(105)/Ile(105 )genotypes. No particular associations with relapse were observed for the GSTP1 polymorphism at codon 114. The risk of relapse when having 1 of the low-risk genotypes (GSTM1 null, GSTT1 null, GSTP1 Val(105)/Val(105)) decreased 1.9-fold (OR = 0.53, 95% CI = 0.24-1.19, P =.123), and the risk when having 2 or 3 low-risk genotypes 3.5-fold (OR = 0.29, 95% CI = 0.06-1.37, P =.118), compared with individuals having no low-risk genotype (P for trend =.005). Our results suggest that polymorphisms within genes of the GST superfamily may be associated with risk of relapse in childhood ALL. (Blood. 2000;95:1222-1228)

Long-term outcome of high-dose cytarabine-based consolidation chemotherapy for older patients with acute myelogenous leukemia.

Despite reports of improved response and leukemia-free survival for adults with acute myelogenous leukemia, advanced age remains a significant adverse prognostic factor for both response to induction therapy and prolonged leukemia-free survival. In addition to a high incidence of treatment-related complications, older patients may have other disease characteristics which predict for brief remission duration despite intensive consolidation chemotherapy. We analyzed the long-term results of high-dose cytarabine-anthracycline consolidation chemotherapy in older patients and examined the effect of major prognostic factors including a history of myelodysplasia, increased age, and cytogenetics. One hundred and ten patients age > or = 60 with newly diagnosed acute myelogenous leukemia were enrolled on three sequential studies conducted from 1982 to 1996. Fifty-six patients (51%) achieved a complete remission and were eligible for high-dose cytarabine-based consolidation chemotherapy administered in two to three courses. After a median follow-up of surviving patients for seventeen months, twelve patients remain alive with eleven in continued remission. Median remission duration for all eligible patients is nine months and the actuarial leukemia-free survival is 14 +/- 10%. Toxicity of consolidation therapy included treatment-related death in six patients and serious neurotoxicity in five. When compared to younger patients, patients over age 60 sustained a much higher risk of relapse despite successfully completing intensive consolidation therapy, regardless of whether other adverse prognostic features were present. Advanced age in acute myelogenous leukemia is associated with a significantly higher risk of relapse unmodified by the presence or absence of other adverse disease characteristics. Although older patients tolerated intensive therapy designed to address the high risk of relapse, there was no apparent benefit of high-dose cytarabine consolidation alone as post-remission treatment for acute myelogenous leukemia in this population.

Development of minimally differentiated acute myeloblastic leukemia with novel isochromosome 18p and antecedent aplastic anemia.

We describe a case of acute myeloblastic leukemia with a novel isochromosome 18, i(18)(p10), preceded by aplastic anemia for six months. The patient is a cotton grower chronically exposed to pesticides. The significance of this chromosomal abnormality is unknown. The possible relationship to the preceding history of aplastic anemia and occupational pesticide exposure is speculated on. The possible mechanism of the association of acute leukemia and aplastic anemia is discussed.

Poor prognosis of prethymic phenotype acute lymphoblastic leukemia (pre-T-ALL).

Pre-T-ALL is an important subgroup of ALL with clinical features different from adult T-ALL. Expression of intracytoplasmic CD3 represents the earliest marker for the prethymic phenotype. We studied four consecutive adult patients with this phenotype. Three of the four patients did not respond to the induction chemotherapy with vincristine, daunorubicin, prednisone and asparaginase. They reached a delayed remission only after chemotherapy with cyclophosphamide and cytosine arabinoside. All four patients relapsed 3, 9, 10 and 13 months after diagnosis. One patient died 2 months after relapse, another one 2 months after allogeneic BMT performed in second relapse. We conclude that patients with early T-cell precursor leukemia do not respond adequately to conventional chemotherapy and should be considered as a high-risk subgroup within the T-lineage ALL.

Busulfan, cyclophosphamide and melphalan as conditioning regimen for bone marrow transplantation in children with myelodysplastic syndromes.

As typical disorders of the elderly, myelodysplastic syndromes (MDSs) are relatively unusual in childhood. Nevertheless, up to 17% of cases of pediatric acute myeloid leukemia may have a preleukemic phase. In young patients, the goal of treatment is eradication of the preleukemic malignant clone and reconstitution of normal hematopoiesis. Allogeneic bone marrow transplantation (BMT) has proved to be capable of this, but the optimal conditioning treatment to achieve eradication remains to be defined. Between May 1989 and June 1993, eight consecutive pediatric patients with MDS received a marrow transplant from an HLA-identical, mixed lymphocyte culture (MLC) non-reactive sibling. Diagnosis at time of presentation was refractory anemia with excess of blasts (RAEB) in two patients, RAEB in transformation (RAEB-t) in three, and juvenile chronic myelogenous leukemia (JCML, the pediatric counterpart of adult chronic myelomonocytic leukemia) in the remaining three children. Conditioning regimen consisted of busulfan, cyclophosphamide and melphalan, three alkylating agents potentially capable of killing also dormant preleukemic stem cells. The preparative regimen was very well tolerated, and all patients engrafted promptly. Six out of eight patients (75%) are alive and well with a median observation time of 20 months (range 8-34 months). Serial karyotype monitoring and molecular analyses have demonstrated a full chimerism of donor cells and the complete disappearance of trisomy 8 detected before transplant in three cases. All surviving patients have a Karnofsky score of 100%. One boy, affected by RAEB-t with monosomy 7 resistant to treatment with low-dose ara-C, relapsed 11 months after BMT, evolved in AML and died from progressive leukemia. Another patient with RAEB died on day +95 after BMT due to interstitial pneumonia of unclear etiology. This study confirms that allogeneic BMT is the treatment of choice in pediatric patients with MDS, and suggests that the employed conditioning regimen is a safe and effective means for eradicating the preleukemic malignant clone. Particularly noteworthy is that the three children with JCML obtained a complete remission and one of them is now a long-term survivor.

[Gene diagnosis and successful reversion in a patient with preleukemia].

According to the FAB classification, a patient (case 1) could not be diagnosed as MDS-RA, although she had clinical features of MDS, as compared with another patient (case 2) who was diagnosed as RAS and had abnormal karyotype (20q- and 5q-) of bone marrow (BM) cells. BM cells of the two patients were SCD (sister chromatid differentiation) negative. Rearrangement of c-erbB and c-erbA was found in the genome of the BM cells in both patients, when southern blot hybridization was performed with probe v-erbB+A. Therefore, case 1 could be diagnosed as preleukemia. During a period about 3 years of treatment with the drug stanozolol in case 1 there was good effect and successful reversion was obtained. She had then normal hematologic and cytogenetic patterns of BM and PB and the rearrangement of c-erbB of BM cells also disappeared. She has worked for two years since then. The mechanism of effective treatment and successful reversion was discussed briefly. Probe v-erbB was shown to be useful in investigation of gene diagnosis of preleukemia or MDS (shown elsewhere).

Idiopathic hypereosinophilic syndrome terminating in acute lymphoblastic leukemia.

Idiopathic hypereosinophilic syndrome (IHES) is a heterogeneous group of disorders characterized by multisystem dysfunction and persistent, extreme eosinophilia of unknown cause. We describe a 9-1/2-year-old boy whose course included several unusual clinical features and terminated 2 years after diagnosis in acute lymphoblastic leukemia (ALL). Serial studies suggest that leukemia was not present earlier in his course. We speculate that this child may have had an evolving lymphoproliferative syndrome with a terminal blast crisis to which the eosinophilia was a nonmalignant leukemoid reaction.

Monosomy 7 syndrome in an infant with neurofibromatosis.

A 9-month-old boy with known familial neurofibromatosis type I (NF-1) presented with a clinical and laboratory picture suggestive of juvenile chronic myelomonocytic leukemia (JCMMoL). Chromosomal studies obtained from the bone marrow indicated, however, that he had monosomy 7 syndrome. We believe this is the first reported case of monosomy 7 syndrome in a child with NF in the United States, and that this case complements a recent report of two cases of NF, JCMMoL, and monosomy 7 in Japanese children. Since monosomy 7 syndrome is very difficult to differentiate from JCMMoL or acute nonlymphocytic leukemia (ANLL) unless appropriate chromosomal studies are obtained, we believe it is possible that monosomy 7 may occur with increased frequency in patients with NF-1. Monosomy 7 syndrome might therefore be a significant cause of the known association between NF-1 and nonlymphoid leukemia.

Effects of CSFs in preleukemia.

Based on pre-clinical and in vitro studies demonstrating enhanced granulocytic proliferation and differentiation induced by granulocyte-monocyte and granulocyte-colony stimulating factors (GM-CSF and G-CSF), these recombinant human hormones have been used to treat cytopenic patients with preleukemia [i.e., myelodysplastic syndromes (MDS)]. To date, five studies have been reported using GM-CSF short-term (generally 7-14 days, x 1-5 courses). Thirty-eight of 45 treated patients had improvements in neutrophil counts, 14 had increased reticulocyte counts with three of these individuals having decreased RBC transfusion requirements, and eight had transient increases in platelets. In 12 patients an increase in marrow and/or peripheral blood blasts was noted. Seven patients progressed to acute myeloid leukemia (AML), particularly patients with greater than 15% marrow blasts. In a longer term study, five patients received GM-CSF for 2 to 9 weeks, although only one individual maintained increased neutrophil counts, one developed antibodies to GM-CSF and one evolved into AML. Eighteen patients have been treated for 2 months with G-CSF, 16 of whom had normalization of neutrophil counts with improved marrow maturation, five had increased reticulocyte counts with three having decreased transfusion requirements, no substantial changes in platelet counts were noted. Eleven patients have received maintenance therapy with G-CSF for 6-16 months, ten had persistent increases in neutrophil counts with enhanced marrow myeloid maturation and five had increased reticulocytes. Decreased infectious episodes were notedat times of neutrophil improvements. Four of the 18 individuals have subsequently developed AML after 6-16 months.(ABSTRACT TRUNCATED AT 250 WORDS)